ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in other sections of the labeling:oHypersensitivity Reactions [see Warnings and Precautions (5.1)]oPancreatic Toxicity [see Warnings and Precautions (5.2)]oThrombosis [see Warnings and Precautions (5.3)]oHemorrhage [see Warnings and Precautions (5.4)]oHepatotoxicity, including VOD [see Warnings and Precautions (5.5)]. oHypersensitivity Reactions [see Warnings and Precautions (5.1)]. oPancreatic Toxicity [see Warnings and Precautions (5.2)]. oThrombosis [see Warnings and Precautions (5.3)]. oHemorrhage [see Warnings and Precautions (5.4)]. oHepatotoxicity, including VOD [see Warnings and Precautions (5.5)]. Most common adverse reactions (incidence 20%) are abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage, stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals Ireland Limited at 1-800-520-5568 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of RYLAZE described in the WARNINGS AND PRECAUTIONS reflect exposure in 167 patients administered RYLAZE intramuscularly at various dosages when used in combination with chemotherapy in study JZP458-201 [see Clinical Studies (14)]. These patients received median of courses of RYLAZE (range: 1-15 courses); 65% of patients received at least four courses.The safety of RYLAZE described below and in Table was evaluated in study JZP458-201, multi-cohort study. Patients received RYLAZE administered intramuscularly at dosages of 25 mg/m2 on Monday, Wednesday, and Friday or 25 mg/m2 on Monday and Wednesday, and 50 mg/m2 on Friday, for doses as replacement for single dose of pegaspargase as component of multi-agent chemotherapy [see Clinical Studies (14)]. The patients had median age of 11 years (range: 1-25 years); the majority of patients were male (57%) and White (68%). The patients received median of courses of RYLAZE (range: 1-14 courses); 65% of patients received at least four courses.A fatal adverse reaction (infection) occurred in patient treated with the RYLAZE 25/25/25 mg/m2 dosage. Serious adverse reactions occurred in 60% of patients who received the recommended dosages of RYLAZE. The most frequent nonhematological serious adverse reactions (in >= 5% of patients) were febrile neutropenia, infection, drug hypersensitivity, pyrexia, nausea, dehydration, stomatitis, acute kidney injury, pancreatitis, diarrhea, and viral infection. Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RYLAZE intramuscularly at the recommended dosages. Adverse reactions resulting in permanent discontinuation included pancreatitis (5%), drug hypersensitivity (4%), and infection (1%).All patients treated with the recommended dosages of RYLAZE as component of multi-agent chemotherapy experienced neutropenia, anemia, or thrombocytopenia. The most common nonhematological adverse reactions (incidence 20%) in patients were abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage, stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia. Table shows the common adverse reactions occurring in at least 15% of the patients.Table 3: Adverse Reactions (>= 15% Incidence) in Patients Receiving RYLAZE as Component of Multi-Agent Chemotherapy in Study JZP458-201Adverse ReactionRYLAZE25/25/25 mg/m2 Intramuscular Dosagea (N 33)RYLAZE25/25/50 mg/m2 Intramuscular Dosagea (N 51)All Grades(%)Grades 3-4(%)All Grades(%)Grades 3-4(%)Abnormal liver test 70187527Musculoskeletal pain456354Nausea459478Fatigue36182218Headache360220Infectionb 36152717Febrile neutropenia30302727Pyrexia306200Hemorrhage240276Stomatitis2412274Abdominal pain210252Decreased appetite216276Drug hypersensitivity216242Hyperglycemia213124Diarrhea186254Tachycardia180162Cough150140Dehydration159126Insomnia15040Peripheral neuropathy15060Pancreatitis 1202210Hypokalemia93228 Includes grouped terms: Abnormal liver test: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, transaminases increased; Musculoskeletal pain: arthralgia, back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, pain in extremity; Nausea: nausea, vomiting; Fatigue: fatigue, asthenia; Infection: sepsis, upper respiratory tract infection, enterocolitis infectious, skin infection, bacteremia, paronychia, pneumonia, otitis externa, soft tissue infection, abdominal infection, conjunctivitis, device related infection, folliculitis, lymph gland infection, necrotizing fasciitis, perirectal abscess, peritonsillar abscess, sinusitis, subcutaneous abscess, wound infection; Drug hypersensitivity: drug hypersensitivity, rash, infusion related reaction, lip swelling, periorbital edema, throat irritation, urticaria, dry skin, eczema, erythema, hand dermatitis, rash maculo-papular, rash papular; Hemorrhage: contusion, epistaxis, catheter site hemorrhage, petechiae, hematochezia, menorrhagia, mouth hemorrhage, increased tendency to bruise, rectal hemorrhage; Abdominal pain: abdominal pain, abdominal pain upper; Diarrhea: diarrhea, colitis; Tachycardia: sinus tachycardia, tachycardia; Peripheral neuropathy: peripheral motor neuropathy, neuropathy peripheral, peripheral sensory neuropathy; Pancreatitis: pancreatitis, pancreatitis acute, amylase increased, lipase increased. Includes adverse event terms and laboratory abnormalitiesGrading is based on Common Terminology Criteria for Adverse Events version 5.0. RYLAZE was administered as component of multi-agent chemotherapy regimens on Monday, Wednesday, and Friday schedule.b Does not include the following fatal adverse reactions: infection (N=1). Clinically relevant adverse reactions in 15% of patients who received RYLAZE in combination with chemotherapy included:Gastrointestinal disorders: Abdominal discomfort, abdominal distension, constipation, gastritisGeneral disorders and administration site conditions: Infusion site reaction, injection site reaction, painInfections and infestations: Viral infection, bacterial infection, fungal infectionInvestigations: Antithrombin III decreased, blood cholesterol increased, blood fibrinogen decreased, activated partial thromboplastin time prolongedMetabolism and nutrition disorders: Acidosis, hyperammonemia, hyperphosphatemia, hypertriglyceridemia, hypoglycemiaMusculoskeletal and connective tissue disorders: Bone pain, muscular weakness, muscle spasmsNervous system disorders: Paresthesia, dizziness, gait disturbance, hyperammonemic encephalopathyPsychiatric disorders: Agitation, anxiety, irritabilityRespiratory, thoracic, and mediastinal disorders: Acute respiratory distress syndrome, pulmonary edemaRenal and urinary disorders: Acute kidney injurySkin and subcutaneous disorders: PruritusVascular disorders: Hypertension, hypotension, thrombosis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of RYLAZE. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure:Hepatic: Veno-occlusive disease (VOD).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Asparaginase erwinia chrysanthemi (recombinant)-rywn is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacological effect of RYLAZE is based on the killing of leukemic cells due to depletion of plasma asparagine. Leukemic cells with low expression of asparagine synthetase have reduced ability to synthesize asparagine, and therefore depend on an exogenous source of asparagine for survival.. 12.2 Pharmacodynamics Asparaginase erwinia chrysanthemi (recombinant)-rywn exposure-response relationships and the time course of pharmacodynamic response are unknown.. 12.3 Pharmacokinetics The pharmacokinetic parameters of asparaginase erwinia chrysanthemi (recombinant)-rywn are presented based on serum asparaginase activity (SAA) after administration of RYLAZE in pediatric and young adult patients with ALL or LBL, unless otherwise specified. Asparaginase erwinia chrysanthemi (recombinant)-rywn maximum SAA (Cmax) and area under the SAA-time curve (AUC) increase proportionally over dosage range from 12.5 to 50 mg/m2 (0.25 to times the maximum approved recommended dose of 50 mg/m2). The simulated exposures for asparaginase erwinia chrysanthemi (recombinant)-rywn after administration of the approved recommended dosages in virtual population are summarized in Table 4.Table 4: Simulated RYLAZE Pharmacokinetic Parameters Based on SAAPK ParameterGeometric Mean (%CV) After Last Dose25 mg/m2 IntramuscularlyEvery 48 Hours25/25/50 mg/m2 IntramuscularlyMonday, Wednesday, FridayLast 25 mg/m2 Wednesday morning doseLast 50 mg/m2 Friday afternoon doseCmax (U/mL)2.3 (55%)2.3 (54%)4.1 (57%)Ctrough (U/mL)0.46 (75%)0.3 (75%)a 0.39 (87%)b Ctrough at maximum interval of 58 hours after the last 25 mg/m2 Wednesday morning dose. Ctrough at maximum interval of 67 hours after the last 50 mg/m2 Friday afternoon dose. Absorption The median (min, max) Tmax of asparaginase erwinia chrysanthemi (recombinant)-rywn after intramuscular administration is 12 (8, 24) hours. The mean absolute bioavailability after intramuscular administration is 37% in healthy subjects.Distribution The geometric mean (%CV) volume of distribution of asparaginase erwinia chrysanthemi (recombinant)-rywn is 1.37 L/m2 (47%).Elimination The geometric mean (%CV) clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn is 0.17 L/hour/m2 (42%) and the apparent half-life is 15.9 (11%) hours.Metabolism Asparaginase erwinia chrysanthemi (recombinant)-rywn is expected to be metabolized into small peptides by catabolic pathways. Specific Populations There were no clinically significant differences in the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn based on age (1.4 to 25 years), weight (9 to 131 kg), or sex after the dose was adjusted by body surface area (BSA). The effect of renal and hepatic impairment on the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn has not been studied.Body Surface Area The volume of distribution and clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn increase with increasing BSA (0.44 to 2.53 m2). Racial and Ethnic Groups Black or African American patients had 29% lower clearance which may increase SAA exposure compared to White and Asian patients. There were no clinically significant differences in clearance between Hispanic and Non-Hispanic patients.. 12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of RYLAZE or of other asparaginase erwinia chrysanthemi (recombinant) products.During treatment in Study JZP458-201 (range to 15 courses), 78/166 (47%) of patients treated with RYLAZE intramuscularly developed anti-asparaginase erwinia chrysanthemi (recombinant)-rywn antibodies. The effects of anti-drug antibodies on pharmacokinetics, pharmacodynamics, and effectiveness have not been adequately characterized.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of RYLAZE for the treatment of patients with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) who have developed hypersensitivity to E. coli-derived asparaginase as component of multi-agent chemotherapeutic regimen was evaluated in Study JZP458-201 (NCT04145531), an open-label, multi-cohort, multi-center trial. In this trial, RYLAZE was administered at various dosages and routes of administration every Monday, Wednesday, and Friday for total of doses to replace each dose of pegaspargase.For the 225 evaluable patients, the median age was 10 years (range: 1-25 years); 61% were male and 39% were female; 69% were White, 11% were Black/African American, 4% were Asian, and 16% were of other or unknown race: 187 (83%) patients had experienced hypersensitivity reaction (Grade >= 3) to pegaspargase, and 15 patients (7%) reported silent inactivation.The determination of efficacy was based on demonstration of the achievement and maintenance of nadir serum asparaginase activity (NSAA) above the level of 0.1 U/mL by simulation. Table shows the proportion with NSAA >= 0.1 U/mL for each approved dosage regimen based on simulation in virtual population [see Clinical Pharmacology (12.3)].Table 5: Proportion (95% CI) with NSAA >= 0.1 U/mL by SimulationRYLAZE DosageTrough Sampling Time Proportion withNSAA 0.1 U/mL (95% CI)a 25 mg/m2 intramuscularly every 48 hours48 hours 96.0 (94.4, 97.2)25/25/50 mg/m2 intramuscularly Monday morning/Wednesday morning/Friday afternoonFriday afternoon: 58 hours after 25 mg/m2 Wednesday morning doseb 91.6 (90.4, 92.8)Monday morning: 67 hours after 50 mg/m2 Friday afternoon dosec 91.4 (90.1, 92.6)a Based on 2,000 virtual subjects. Based on maximum interval of 58 hours between the Wednesday morning and Friday afternoon doses. Based on maximum interval of 67 hours between the Friday afternoon and Monday morning doses.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS RYLAZE is contraindicated in patients with:oHistory of serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis [see Warnings and Precautions (5.1)];oHistory of serious pancreatitis during previous asparaginase therapy [see Warnings and Precautions (5.2)];oHistory of serious thrombosis during previous asparaginase therapy [see Warnings and Precautions (5.3)];oHistory of serious hemorrhagic events during previous asparaginase therapy [see Warnings and Precautions (5.4)];oSevere hepatic impairment [see Warnings and Precautions (5.5)]. oHistory of serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis [see Warnings and Precautions (5.1)];. oHistory of serious pancreatitis during previous asparaginase therapy [see Warnings and Precautions (5.2)];. oHistory of serious thrombosis during previous asparaginase therapy [see Warnings and Precautions (5.3)];. oHistory of serious hemorrhagic events during previous asparaginase therapy [see Warnings and Precautions (5.4)];. oSevere hepatic impairment [see Warnings and Precautions (5.5)]. RYLAZE is contraindicated in patients with:oHistory of serious hypersensitivity reactions to RYLAZE, including anaphylaxis. (4)oHistory of serious pancreatitis during previous L-asparaginase therapy. (4)oHistory of serious thrombosis during previous L-asparaginase therapy. (4)oHistory of serious hemorrhagic events during previous L-asparaginase therapy. (4)oSevere hepatic impairment. (4). oHistory of serious hypersensitivity reactions to RYLAZE, including anaphylaxis. (4). oHistory of serious pancreatitis during previous L-asparaginase therapy. (4). oHistory of serious thrombosis during previous L-asparaginase therapy. (4). oHistory of serious hemorrhagic events during previous L-asparaginase therapy. (4). oSevere hepatic impairment. (4).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION There are two RYLAZE regimens that can be used to replace long-acting asparaginase product. The recommended dosages of RYLAZE are: When administered every 48 hourso25 mg/m2 intramuscularly every 48 hours; When administered Monday/Wednesday/Fridayo25 mg/m2 intramuscularly on Monday morning and Wednesday morning and 50 mg/m2 intramuscularly on Friday afternoon. (2.1). o25 mg/m2 intramuscularly every 48 hours; o25 mg/m2 intramuscularly on Monday morning and Wednesday morning and 50 mg/m2 intramuscularly on Friday afternoon. (2.1). 2.1 Recommended Dosage There are two RYLAZE regimens that can be used to replace long-acting asparaginase product. The recommended dosages of RYLAZE are: When administered every 48 hours: o25 mg/m2 administered intramuscularly every 48 hours; When administered on Monday/Wednesday/Friday schedule: o25 mg/m2 intramuscularly on Monday morning and Wednesday morning, and 50 mg/m2 intramuscularly on Friday afternoon. Administer the Friday afternoon dose 53 to 58 hours after the Wednesday morning dose (e.g., 8:00 am on Monday and Wednesday, and 1:00 pm to 6:00 pm on Friday) [see Clinical Pharmacology (12.3), Clinical Studies (14)].Table shows the number of RYLAZE dosages recommended for the intended duration of treatment for replacement of one dose of calaspargase pegol products (3 weeks of asparaginase coverage) or one dose of pegaspargase products (2 weeks of asparaginase coverage). See the full prescribing information for the long-acting asparaginase product to determine the total duration of administration of RYLAZE as replacement therapy.Table 1: Recommended Duration of RYLAZE Dosing to Replace One Long-Acting Asparaginase DoseWhen RYLAZE is Administered:Recommended Duration of RYLAZE to Replace Calaspargase Pegol ProductsRecommended Duration of RYLAZE to Replace Pegaspargase Products25 mg/m2 intramuscular every 48 hoursReplace one dose of calaspargase pegol products with 11 doses of RYLAZEReplace one dose of pegaspargase products with doses of RYLAZE25 mg/m2 intramuscular on Monday morning and Wednesday morning, and 50 mg/m2 intramuscular on Friday afternoonReplace one dose of calaspargase pegol products with doses of RYLAZEReplace one dose of pegaspargase products with doses of RYLAZESee bullet above for timing of 25/25/50 mg/m2 dosing of RYLAZE.. o25 mg/m2 administered intramuscularly every 48 hours; o25 mg/m2 intramuscularly on Monday morning and Wednesday morning, and 50 mg/m2 intramuscularly on Friday afternoon. Administer the Friday afternoon dose 53 to 58 hours after the Wednesday morning dose (e.g., 8:00 am on Monday and Wednesday, and 1:00 pm to 6:00 pm on Friday) [see Clinical Pharmacology (12.3), Clinical Studies (14)].. 2.2 Recommended Premedication Premedicate patients with acetaminophen, an H-1 receptor blocker (such as diphenhydramine), and an H-2 receptor blocker (such as famotidine) 30-60 minutes prior to administration of RYLAZE to decrease the risk and severity of hypersensitivity reactions [see Warnings and Precautions (5.1)].. 2.3 Recommended Monitoring and Dosage Modifications for Adverse Reactions Monitor patients bilirubin, transaminases, glucose, and clinical examinations prior to treatment every 2-3 weeks and as indicated clinically. If results are abnormal, monitor patients until recovery from the cycle of therapy. If an adverse reaction occurs, modify treatment according to Table 2.Table 2: Dosage ModificationsAdverse ReactionSeverityActionHypersensitivity Reaction [see Warnings and Precautions (5.1)] Grade 2oTreat the symptoms.Grade to 4oDiscontinue RYLAZE permanently.Pancreatitis [see Warnings and Precautions (5.2)] Grade to 4oHold RYLAZE for elevations in lipase or amylase 2 times the ULN, or for symptomatic pancreatitis.oResume treatment when lipase and amylase are 1.5 times the ULN and symptoms are resolved.oDiscontinue RYLAZE permanently if clinical necrotizing or hemorrhagic pancreatitis is confirmed.Thrombosis [see Warnings and Precautions (5.3)] Uncomplicated thrombosisoHold RYLAZE.oTreat with appropriate antithrombotic therapy.oUpon resolution of symptoms, consider resuming RYLAZE, while continuing antithrombotic therapy.Severe or life-threatening thrombosisoDiscontinue RYLAZE permanently.oTreat with appropriate antithrombotic therapy.Hemorrhage [see Warnings and Precautions (5.4)] Grade to 4oHold RYLAZE.oEvaluate for coagulopathy and consider clotting factor replacement as needed.oResume RYLAZE with the next scheduled dose if bleeding is controlled.Hepatotoxicity [see Warnings and Precautions (5.5)] Total bilirubin 3 times to <= 10 times the ULNoHold RYLAZE until total bilirubin levels decrease to <= 1.5 times the ULN.Total bilirubin 10 times the ULNoDiscontinue RYLAZE and do not make up missed doses. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Upper limit of normal. oTreat the symptoms.. oDiscontinue RYLAZE permanently.. oHold RYLAZE for elevations in lipase or amylase 2 times the ULN, or for symptomatic pancreatitis.. oResume treatment when lipase and amylase are 1.5 times the ULN and symptoms are resolved.. oDiscontinue RYLAZE permanently if clinical necrotizing or hemorrhagic pancreatitis is confirmed.. oHold RYLAZE.. oTreat with appropriate antithrombotic therapy.. oUpon resolution of symptoms, consider resuming RYLAZE, while continuing antithrombotic therapy.. oDiscontinue RYLAZE permanently.. oTreat with appropriate antithrombotic therapy.. oHold RYLAZE.. oEvaluate for coagulopathy and consider clotting factor replacement as needed.. oResume RYLAZE with the next scheduled dose if bleeding is controlled.. oHold RYLAZE until total bilirubin levels decrease to <= 1.5 times the ULN.. oDiscontinue RYLAZE and do not make up missed doses.. 2.4 Preparation and Administration Instructions Ensure that medical support is available to appropriately manage anaphylactic reactions when administering RYLAZE [see Warnings and Precautions (5.1)].Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter, cloudiness, or discoloration are present, discard the vial. oUse aseptic technique.oDetermine the dose, total volume of RYLAZE solution required, and the number of RYLAZE vials needed based on the individual patients BSA. More than one vial may be needed for full dose.oWithdraw the indicated injection volume of RYLAZE into the syringe for injection.oDo not shake the vial.oLimit the volume of RYLAZE at single injection site to mL.oIf the volume to be administered is greater than mL, divide the doses equally into multiple syringes, one for each injection site.oDiscard the remaining unused RYLAZE in the single-dose vial.oAdminister RYLAZE by intramuscular injection.oRotate injection sites.oDo not inject RYLAZE into scar tissue or areas that are reddened, inflamed, or swollen.oIf the prepared dose is not used immediately, store the syringe(s) at room temperature 15C to 25C (59F to 77F) for up to hours or refrigerated at 2C to 8C (36F to 46F) for up to 24 hours. The syringe does not need to be protected from light during storage.. oUse aseptic technique.. oDetermine the dose, total volume of RYLAZE solution required, and the number of RYLAZE vials needed based on the individual patients BSA. More than one vial may be needed for full dose.. oWithdraw the indicated injection volume of RYLAZE into the syringe for injection.oDo not shake the vial.oLimit the volume of RYLAZE at single injection site to mL.oIf the volume to be administered is greater than mL, divide the doses equally into multiple syringes, one for each injection site.oDiscard the remaining unused RYLAZE in the single-dose vial.. oDo not shake the vial.. oLimit the volume of RYLAZE at single injection site to mL.. oIf the volume to be administered is greater than mL, divide the doses equally into multiple syringes, one for each injection site.. oDiscard the remaining unused RYLAZE in the single-dose vial.. oAdminister RYLAZE by intramuscular injection.oRotate injection sites.oDo not inject RYLAZE into scar tissue or areas that are reddened, inflamed, or swollen.. oRotate injection sites.. oDo not inject RYLAZE into scar tissue or areas that are reddened, inflamed, or swollen.. oIf the prepared dose is not used immediately, store the syringe(s) at room temperature 15C to 25C (59F to 77F) for up to hours or refrigerated at 2C to 8C (36F to 46F) for up to 24 hours. The syringe does not need to be protected from light during storage.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION oHypersensitivity Inform patients of the risk of allergic reactions, including anaphylaxis. Instruct the patient on the symptoms of allergic reactions and to seek medical advice immediately if they experience such symptoms [see Warnings and Precautions (5.1)]. oPancreatitis Instruct patients on signs and symptoms of pancreatitis and to seek medical attention if they experience severe abdominal pain [see Warnings and Precautions (5.2)]. oThrombosis Instruct patients on the risk of thrombosis and to seek medical advice immediately if they experience headache, arm or leg swelling, shortness of breath, and chest pain [see Warnings and Precautions (5.3)]. oHemorrhage Advise patients to report any unusual bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.4)].oHepatotoxicity, including Veno-Occlusive Liver Disease Inform patients that liver problems, including severe, life-threatening, or fatal VOD and abnormalities in liver tests, may develop during RYLAZE treatment. Advise patients to report any jaundice, severe nausea or vomiting, or easy bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.5)].oPregnancy Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with RYLAZE and for months after the last dose [see Use in Specific Populations (8.3)].oLactation Advise women not to breastfeed during treatment with RYLAZE and for week after the last dose [see Use in Specific Populations (8.2)].Manufactured by: Jazz Pharmaceuticals Ireland LimitedDublin, IrelandU.S. License No. 2167 Distributed by:Jazz Pharmaceuticals, Inc.Palo Alto, CA 94306 Protected by U.S. Patent nos. 8,288,127 and 10,787,671RYLAZE(R) is trademark of Jazz Pharmaceuticals plc or its subsidiaries.(C)2024 Jazz Pharmaceuticals. oHypersensitivity Inform patients of the risk of allergic reactions, including anaphylaxis. Instruct the patient on the symptoms of allergic reactions and to seek medical advice immediately if they experience such symptoms [see Warnings and Precautions (5.1)]. oPancreatitis Instruct patients on signs and symptoms of pancreatitis and to seek medical attention if they experience severe abdominal pain [see Warnings and Precautions (5.2)]. oThrombosis Instruct patients on the risk of thrombosis and to seek medical advice immediately if they experience headache, arm or leg swelling, shortness of breath, and chest pain [see Warnings and Precautions (5.3)]. oHemorrhage Advise patients to report any unusual bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.4)].. oHepatotoxicity, including Veno-Occlusive Liver Disease Inform patients that liver problems, including severe, life-threatening, or fatal VOD and abnormalities in liver tests, may develop during RYLAZE treatment. Advise patients to report any jaundice, severe nausea or vomiting, or easy bleeding or bruising to their healthcare provider [see Warnings and Precautions (5.5)].. oPregnancy Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (8.1)].. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with RYLAZE and for months after the last dose [see Use in Specific Populations (8.3)].. oLactation Advise women not to breastfeed during treatment with RYLAZE and for week after the last dose [see Use in Specific Populations (8.2)].

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage There are two RYLAZE regimens that can be used to replace long-acting asparaginase product. The recommended dosages of RYLAZE are: When administered every 48 hours: o25 mg/m2 administered intramuscularly every 48 hours; When administered on Monday/Wednesday/Friday schedule: o25 mg/m2 intramuscularly on Monday morning and Wednesday morning, and 50 mg/m2 intramuscularly on Friday afternoon. Administer the Friday afternoon dose 53 to 58 hours after the Wednesday morning dose (e.g., 8:00 am on Monday and Wednesday, and 1:00 pm to 6:00 pm on Friday) [see Clinical Pharmacology (12.3), Clinical Studies (14)].Table shows the number of RYLAZE dosages recommended for the intended duration of treatment for replacement of one dose of calaspargase pegol products (3 weeks of asparaginase coverage) or one dose of pegaspargase products (2 weeks of asparaginase coverage). See the full prescribing information for the long-acting asparaginase product to determine the total duration of administration of RYLAZE as replacement therapy.Table 1: Recommended Duration of RYLAZE Dosing to Replace One Long-Acting Asparaginase DoseWhen RYLAZE is Administered:Recommended Duration of RYLAZE to Replace Calaspargase Pegol ProductsRecommended Duration of RYLAZE to Replace Pegaspargase Products25 mg/m2 intramuscular every 48 hoursReplace one dose of calaspargase pegol products with 11 doses of RYLAZEReplace one dose of pegaspargase products with doses of RYLAZE25 mg/m2 intramuscular on Monday morning and Wednesday morning, and 50 mg/m2 intramuscular on Friday afternoonReplace one dose of calaspargase pegol products with doses of RYLAZEReplace one dose of pegaspargase products with doses of RYLAZESee bullet above for timing of 25/25/50 mg/m2 dosing of RYLAZE.. o25 mg/m2 administered intramuscularly every 48 hours; o25 mg/m2 intramuscularly on Monday morning and Wednesday morning, and 50 mg/m2 intramuscularly on Friday afternoon. Administer the Friday afternoon dose 53 to 58 hours after the Wednesday morning dose (e.g., 8:00 am on Monday and Wednesday, and 1:00 pm to 6:00 pm on Friday) [see Clinical Pharmacology (12.3), Clinical Studies (14)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Advise not to breastfeed. (8.2). oLactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, RYLAZE can cause fetal harm when administered to pregnant woman. There are no available data on RYLAZE use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive and developmental toxicity studies, intramuscular administration of asparaginase Erwinia chrysanthemi to pregnant rats and rabbits during organogenesis resulted in structural abnormalities and embryo-fetal mortality (see Data) at exposures below those in patients at the recommended human dose. Advise pregnant women of the potential risk to fetus. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.Data Animal DataAnimal reproductive and developmental toxicity studies have not been conducted with RYLAZE.In embryofetal development studies, asparaginase Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 3, 6, or 12 mg/m2) and rabbits (at 0.12, 0.30, or 0.48 mg/m2). In rats given 12 mg/m2 (approximately 0.48 times the maximum recommended human dose), maternal toxicity of decreased body weight gain was observed, as was fetal finding of increased incidence of partially undescended thymic tissue. In rabbits, maternal toxicity consisting of decreased body weight was observed at 0.48 mg/m2 (approximately 0.02 times the maximum recommended human dose). Increased post-implantation loss, decrease in the number of live fetuses, and gross abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) were observed at doses of >= 0.12 mg/m2 (approximately 0.005 times the maximum recommended human dose).. 8.2 Lactation Risk SummaryThere are no data on the presence of asparaginase erwinia chrysanthemi (recombinant)-rywn in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with RYLAZE and for week after the last dose.. 8.3 Females and Males of Reproductive Potential RYLAZE can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy Testing Pregnancy testing is recommended in females of reproductive potential prior to initiating RYLAZE.Contraception Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with RYLAZE and for months after the last dose.. 8.4 Pediatric Use The safety and effectiveness of RYLAZE in the treatment of ALL and LBL have been established in pediatric patients month to 17 years who have developed hypersensitivity to long-acting E. coli-derived asparaginase. Use of RYLAZE in these age groups is supported by evidence from an adequate and well-controlled study in adults and pediatric patients. The trial included 139 pediatric patients, including infants (1 month to 2 years), 99 children (2 years to 12 years old), and 38 adolescents (12 years to 17 years old). There were no clinically meaningful differences in safety or nadir serum asparaginase activity across age groups. The safety and effectiveness of RYLAZE have not been established in pediatric patients younger than month of age.. 8.5 Geriatric Use Clinical studies of RYLAZE did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypersensitivity: Monitor for signs or symptoms. Discontinue RYLAZE for serious reaction. (5.1)oPancreatitis: Monitor for symptoms. Discontinue if pancreatitis occurs. (5.2)oThrombosis: Discontinue RYLAZE for severe or life-threatening thrombosis. Provide anticoagulation therapy as indicated. (5.3)oHemorrhage: Discontinue RYLAZE for severe or life-threatening hemorrhage. (5.4)oHepatotoxicity, including hepatic veno-occlusive disease: Discontinue RYLAZE for grade increases of bilirubin. (5.5). oHypersensitivity: Monitor for signs or symptoms. Discontinue RYLAZE for serious reaction. (5.1). oPancreatitis: Monitor for symptoms. Discontinue if pancreatitis occurs. (5.2). oThrombosis: Discontinue RYLAZE for severe or life-threatening thrombosis. Provide anticoagulation therapy as indicated. (5.3). oHemorrhage: Discontinue RYLAZE for severe or life-threatening hemorrhage. (5.4). oHepatotoxicity, including hepatic veno-occlusive disease: Discontinue RYLAZE for grade increases of bilirubin. (5.5). 5.1 Hypersensitivity Reactions Hypersensitivity reactions after the use of RYLAZE occurred in 29% of patients in clinical trials, and it was severe in 6% of patients [see Adverse Reactions (6.1)]. Anaphylaxis was observed in 2% of patients after intramuscular administration. Discontinuation of RYLAZE due to hypersensitivity reactions occurred in 5% of patients. Hypersensitivity reactions were higher in patients who received intravenous asparaginase erwinia chrysanthemi (recombinant)-rywn. The intravenous route of administration is not approved.In patients administered RYLAZE intramuscularly in clinical trials, the median number of doses of RYLAZE that patients received prior to the onset of the first hypersensitivity reaction was 12 doses (range: 1-64 doses). The most commonly observed reaction was rash (19%), and patient (1%) experienced severe rash. Hypersensitivity reactions observed with L-asparaginase class products include angioedema, urticaria, lip swelling, eye swelling, rash or erythema, blood pressure decreased, bronchospasm, dyspnea, and pruritus.Premedicate patients prior to administration of RYLAZE as recommended [see Dosage and Administration (2.2)]. Because of the risk of serious allergic reactions (e.g., life-threatening anaphylaxis), administer RYLAZE in setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, oxygen, intravenous steroids, antihistamines) [see Dosage and Administration (2.3)]. Discontinue RYLAZE in patients with serious hypersensitivity reactions [see Dosage and Administration (2.3)].. 5.2 Pancreatitis Pancreatitis, including elevated amylase or lipase, was reported in 20% of patients in clinical trials of RYLAZE and was severe in 8% [see Adverse Reactions (6.1)]. Symptomatic pancreatitis occurred in 7% of patients, and it was severe in 6% of patients. Elevated amylase or lipase without symptomatic pancreatitis was observed in 13% of patients treated with RYLAZE. Hemorrhagic or necrotizing pancreatitis have been reported with L-asparaginase class products.Inform patients of the signs and symptoms of pancreatitis, which, if left untreated, could be fatal. Evaluate patients with symptoms compatible with pancreatitis to establish diagnosis. Assess serum amylase and lipase levels in patients with any signs or symptoms of pancreatitis. Discontinue RYLAZE in patients with severe or hemorrhagic pancreatitis. In the case of mild pancreatitis, withhold RYLAZE until the signs and symptoms subside and amylase and/or lipase levels return to 1.5 times the ULN [see Dosage and Administration 2.3 )]. After resolution of mild pancreatitis, treatment with RYLAZE may be resumed.. 5.3 Thrombosis Serious thrombotic events, including sagittal sinus thrombosis and pulmonary embolism, have been reported in 1% of patients following treatment with RYLAZE. Discontinue RYLAZE for thrombotic event, and administer appropriate antithrombotic therapy. Consider resumption of treatment with RYLAZE only if the patient had an uncomplicated thrombosis [see Dosage and Administration 2.3 )].. 5.4 Hemorrhage Bleeding was reported in 25% of patients treated with RYLAZE, and it was severe in 2%. Most commonly observed reactions were bruising (12%) and nose bleed (9%) [see Adverse Reactions (6.1)].In patients treated with L-asparaginase class products, hemorrhage may be associated with increased prothrombin time (PT), increased partial thromboplastin time (PTT), and hypofibrinogenemia. Consider appropriate replacement therapy in patients with severe or symptomatic coagulopathy [see Dosage and Administration 2.3 )].. 5.5 Hepatotoxicity, including Hepatic Veno-Occlusive Disease Elevated bilirubin and/or transaminases occurred in 75% of patients treated with RYLAZE in clinical trials, and 26% had Grade >= elevations. Elevated bilirubin occurred in 28% of patients treated with RYLAZE in clinical trials, and 2% had Grade >= elevations. Elevated transaminases occurred in 73% of patients treated with RYLAZE in clinical trials, and 25% had Grade >= elevations [see Adverse Reactions (6.1)].Hepatotoxicity, including severe, life-threatening, and potential fatal cases of hepatic veno-occlusive disease (VOD), have been observed in patients treated with asparaginase class products in combination with standard chemotherapy, including during the induction phase of multiphase chemotherapy [see Adverse Reactions (6)]. Do not administer RYLAZE to patients with severe hepatic impairment [see Contraindication (4)]. Inform patients of the signs and symptoms of hepatotoxicity. Evaluate bilirubin and transaminases prior to each cycle of RYLAZE and at least weekly during cycles of treatment that include RYLAZE, through four weeks after the last dose of RYLAZE. Monitor frequently for signs and symptoms of hepatic VOD, which may include rapid weight gain, fluid retention with ascites, hepatomegaly (which may be painful), and rapid increase of bilirubin. For patients who develop abnormal liver tests after RYLAZE, more frequent monitoring for liver test abnormalities and clinical signs and symptoms of VOD is recommended. In the event of serious liver toxicity, including VOD, discontinue treatment with RYLAZE and provide supportive care [see Dosage and Administration (2.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The pharmacokinetic parameters of asparaginase erwinia chrysanthemi (recombinant)-rywn are presented based on serum asparaginase activity (SAA) after administration of RYLAZE in pediatric and young adult patients with ALL or LBL, unless otherwise specified. Asparaginase erwinia chrysanthemi (recombinant)-rywn maximum SAA (Cmax) and area under the SAA-time curve (AUC) increase proportionally over dosage range from 12.5 to 50 mg/m2 (0.25 to times the maximum approved recommended dose of 50 mg/m2). The simulated exposures for asparaginase erwinia chrysanthemi (recombinant)-rywn after administration of the approved recommended dosages in virtual population are summarized in Table 4.Table 4: Simulated RYLAZE Pharmacokinetic Parameters Based on SAAPK ParameterGeometric Mean (%CV) After Last Dose25 mg/m2 IntramuscularlyEvery 48 Hours25/25/50 mg/m2 IntramuscularlyMonday, Wednesday, FridayLast 25 mg/m2 Wednesday morning doseLast 50 mg/m2 Friday afternoon doseCmax (U/mL)2.3 (55%)2.3 (54%)4.1 (57%)Ctrough (U/mL)0.46 (75%)0.3 (75%)a 0.39 (87%)b Ctrough at maximum interval of 58 hours after the last 25 mg/m2 Wednesday morning dose. Ctrough at maximum interval of 67 hours after the last 50 mg/m2 Friday afternoon dose. Absorption The median (min, max) Tmax of asparaginase erwinia chrysanthemi (recombinant)-rywn after intramuscular administration is 12 (8, 24) hours. The mean absolute bioavailability after intramuscular administration is 37% in healthy subjects.Distribution The geometric mean (%CV) volume of distribution of asparaginase erwinia chrysanthemi (recombinant)-rywn is 1.37 L/m2 (47%).Elimination The geometric mean (%CV) clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn is 0.17 L/hour/m2 (42%) and the apparent half-life is 15.9 (11%) hours.Metabolism Asparaginase erwinia chrysanthemi (recombinant)-rywn is expected to be metabolized into small peptides by catabolic pathways. Specific Populations There were no clinically significant differences in the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn based on age (1.4 to 25 years), weight (9 to 131 kg), or sex after the dose was adjusted by body surface area (BSA). The effect of renal and hepatic impairment on the pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant)-rywn has not been studied.Body Surface Area The volume of distribution and clearance of asparaginase erwinia chrysanthemi (recombinant)-rywn increase with increasing BSA (0.44 to 2.53 m2). Racial and Ethnic Groups Black or African American patients had 29% lower clearance which may increase SAA exposure compared to White and Asian patients. There were no clinically significant differences in clearance between Hispanic and Non-Hispanic patients.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, RYLAZE can cause fetal harm when administered to pregnant woman. There are no available data on RYLAZE use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive and developmental toxicity studies, intramuscular administration of asparaginase Erwinia chrysanthemi to pregnant rats and rabbits during organogenesis resulted in structural abnormalities and embryo-fetal mortality (see Data) at exposures below those in patients at the recommended human dose. Advise pregnant women of the potential risk to fetus. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are to 4% and 15 to 20%, respectively.Data Animal DataAnimal reproductive and developmental toxicity studies have not been conducted with RYLAZE.In embryofetal development studies, asparaginase Erwinia chrysanthemi was administered intramuscularly every other day during the period of organogenesis to pregnant rats (at 3, 6, or 12 mg/m2) and rabbits (at 0.12, 0.30, or 0.48 mg/m2). In rats given 12 mg/m2 (approximately 0.48 times the maximum recommended human dose), maternal toxicity of decreased body weight gain was observed, as was fetal finding of increased incidence of partially undescended thymic tissue. In rabbits, maternal toxicity consisting of decreased body weight was observed at 0.48 mg/m2 (approximately 0.02 times the maximum recommended human dose). Increased post-implantation loss, decrease in the number of live fetuses, and gross abnormalities (e.g., absent kidney, absent accessory lung lobe, additional subclavian artery, and delayed ossification) were observed at doses of >= 0.12 mg/m2 (approximately 0.005 times the maximum recommended human dose).